Cortisol is a regulator of maturation of fetal organs, including the heart. Maternal hypercortisolemia or stress appears to increase the risk of stillbirth at term and alter growth of the fetal heart. In an animal model with elevated maternal cortisol in late gestation, mimicking mild but chronic stress, we have found a striking increase in stillbirth and changes in gene expression in the fetal heart suggesting changes in glucose metabolism, mitochondrial function, and energy availability. The data support the hypothesis that there is downregulation of TCA cycle activity and mitochondrial number and function. The proposed studies will test the overarching hypothesis that alterations in fetal cortisol alter cardiac metabolism, function and remodeling in late gestation, and ultimately lead to fetal cardiac dysfunction, including both structural and functional changes, that result in adverse events during labor and delivery or in the immediate postnatal period. We will test for progressive changes in pathophysiology in the fetal heart during controlled labor using radiotelemetric monitoring of fetal aortic pressure and ECG, ultrasound analysis of fetal heart dimensions and function, and transcriptomic, metabolomic, histopathologic, and biochemical approaches to investigate changes in cardiac structure and metabolism. We will test the hypothesis that there is disruption of normal pathways for glucose and lactate metabolism and loss of mitochondrial function that will be reflected in changes in mitochondrial respirometry, gene expression and metabolomics. We will test the hypothesis that there will be pathophysiologic changes in cardiac structure and function that will be reflected by changes in ventricular dimensions and function identified by echocardiography, as well as alterations in aortic pressure, and in ECG. We will also test for alterations in glucose utilization by the heart using 13C glucose flux and identification of 13C glucose isoptomers in plasma and in the heart tissue. We will further test the hypothesis that changes in cardiac metabolism and mitochondria underlie changes in cardiac metabolism and ECG changes using administration of dichloroacetate, a small molecule therapeutic that increases activity of the pyruvate dehydrogenase complex, which is required for TCA cycle activity. DCA will be administered acutely during labor, the time at which the abnormalities in ECG become evident in our model. DCA is used in humans with mitochondrial diseases, including children with lactic acidosis, and the data from this study would potentially provide a therapeutic method for acute rescue of neonates.

Public Health Relevance

Maternal stress or hypercortisolemia are both thought to increase the risk of stillbirth and to have effects on the fetal heart at term. The proposed studies will test the hypothesis that increases in maternal stress hormone cortisol in late gestation leads to progressive changes in metabolism of glucose and growth of the fetal heart, culminating in mitochondrial loss, heart failure and/or arrhythmias at the time of labor and delivery.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD087306-02
Application #
9399677
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Ilekis, John V
Project Start
2016-12-14
Project End
2021-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Florida
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611